We have used patch clamp techniques to investigate the effects of two important classes of inhibitory neuropeptides on electrical excitability of the molecular level in a tumor cell line from rat pituitary. Both classes of neuropeptides inhibit dihydropyridine-sensitive calcium channels and stimulate charybdotoxin-sensitive potassium channels by reversing the effects of cyclic AMP-dependent phosphorylation at a step distal to cyclic AMP synthesis or degradation. Experiments with phosphatase inhibitors and purified enzymes implicate the polycation-stimulated phosphoserine protein phosphatase 2A as the final common effector on both types of channel proteins. Natriuretic peptides activate phosphatase 2A through a cyclic GMP-dependent protein kinase. Many other neuropeptides, like somatostatin, that act through pertussis toxin-sensitive G-proteins, stimulate phosphatase 2A through a lipoxygenase metabolite of arachidonic acid. We are currently pursuing the generality of these novel and important inhibitory signalling pathways.